Descriptions

The ovine sexually dimorphic nucleus (oSDN) is 2 times larger in rams than in ewes. Sexual
differentiation of the oSDN is produced by testosterone exposure during the critical period
occurring between gestational day (GD)60 and GD90 (term, 147 d). We tested the hypothesis
that testosterone acts through the androgen receptor to control development of the male-typical
oSDN. In experiment 1, pregnant ewes received injections of vehicle, androgen receptor
antagonist flutamide, or nonaromatizable androgen dihydrotestosterone (DHT) propionate
during the critical period. Fetuses were delivered at GD135. Both antagonist and agonist
treatments significantly reduced mean oSDN volume in males but had no effects in females.
Experiment 2, we analyzed the effect of treatments on the fetal hypothalamic-pituitary-gonadal
axis to determine whether compensatory changes in hormone secretion occurred that
could explain the effect of DHT. Pregnant ewes were injected with vehicle, flutamide, or DHT
propionate from GD60 to GD84, and fetuses were delivered on GD85. Flutamide significantly
increased LH and testosterone in males, whereas DHT significantly decreased both hormones.
In females, LH was unaffected by flutamide but significantly reduced by DHT exposure. DHT
significantly decreased pituitary gonadotropin and hypothalamic kisspeptin mRNA expression
in males and females. These results suggest that androgen receptor mediates the effect of
testosterone on oSDN masculinization, because this process was blocked by the androgen
receptor antagonist flutamide in eugonadal males. In contrast, the reduction of oSDN volume
observed after DHT exposure appears to be mediated by a negative feedback mechanism
exerted on the hypothalamus to reduce LH and testosterone secretion. The reduced androgen
exposure most likely accounted for the decreased oSDN volume. We conclude that, during the
critical period, the male reproductive axis in long gestation species, such as sheep, is sufficiently
developed to react to perturbations in serum androgens and mitigate disruptions in brain
masculinization.